Tricyclic benzodiazepines

ABSTRACT

Tricyclic benzodiazepine derivatives (A) bearing a hydroxylower alkyl substituent in the 1-position and a heterocyclic ring joined between positions 4 and 5 of the benzodiazepine moiety are described. The heterocyclic ring will contain the nitrogen atom appearing at position 4 of the benzodiazepine ring as well as the hetero atom, which may be either oxygen or nitrogen, attached to the carbon atom at the 5-position of the benzodiazepine ring. A bearing an oxygen atom in the new heterocyclic ring may be formed from the corresponding 4,5-unsaturated benzodiazepines by treatment with an epoxide compound in the presence of an acid catalyst. A bearing either a nitrogen or an oxygen atom in the new heterocyclic ring may be prepared by cyclization of the corresponding open compound. A are useful as sedative, muscle relaxant and anti-convulsant agents.

CROSS REFERENCE TO RELATED APPLICATIONS

The subject application is a division of U.S. application Ser. No.557,438 filed Mar. 11, 1975 now U.S. Pat. No. 3,965,151 issued June 22,1976 which is a division of U.S. application Ser. No. 45,928 filed June12, 1970, now abandoned which is further a continuation-in-partapplication of U.S. application Ser. No. 26,068, filed Apr. 6, 1970 nowU.S. Pat. No. 3,905,965 issued Sept. 16, 1975 which is in turn acontinuation-in-part of U.S. application Ser. No. 863,377 filed Oct. 2,1969, now abandoned which is in turn a continuation-in-part of U.S.application Ser. No. 768,909 filed Oct. 18, 1968, now abandoned.

DESCRIPTION OF THE INVENTION

The present invention relates to tricyclic benzodiazepines of thefollowing formula ##STR1## wherein A is selected from the groupconsisting of ##STR2## Z is a hetero atom selected from the groupconsisting of ##STR3## where R₆ is hydrogen, lower alkyl or acyl; n isan integer from 1 to 2; R₁ is hydrogen, halogen, nitro, trifluoromethyl,lower alkyl, lower alkyl mercapto or lower alkoxy; R₃ is hydrogen, loweralkyl or the group --COO-lower alkyl; R₄ is hydrogen, lower alkyl or--CH₂ X where X is selected from the group consisting of chlorine,bromine, lower alkoxy, lower alkoxy-lower alkyl and di-lower alkylamino;and R₅ is pyridyl, phenyl and phenyl substituted with a member selectedfrom the group consisting of halogen, nitro, trifluoromethyl, and loweralkyl.

As used herein, the term "lower alkyl", either alone or in combinationas in lower alkoxy-lower alkyl, comprehends straight or branched chainhydrocarbon groups having from 1-7 carbon atoms, preferably 1-4 carbonatoms, such as methyl, ethyl, propyl, isopropyl and the like. The term"acyl" encompasses an organic radical derived by removal of a hydroxylgroup from an organic acid, such as an alkanoic acid containing from 2-7carbon atoms, for example propionyl and the like. The term "loweralkoxy" comprehends a lower alkyl group having an oxygen functionsubstituted therein, such as methoxy, ethoxy, propoxy, etc. The term"halogen" represents all four forms thereof, i.e. fluorine, chlorine,bromine and iodine, unless expressly indicated otherwise. The term"lower alkanol" connotes, primary, secondary, or tertiary saturatedaliphatic alcohols such as methanol, ethanol, propanol, isopropanol andthe like.

A preferred group of compounds falling within the scope of formula I arethose wherein the hetero atom Z is oxygen, i.e. compounds of the formula##STR4## wherein A, R₁, R₃ -R₅, and n are as described above.

Another preferred embodiment of the present invention encompasses thecompounds of formula I wherein the hetero atom Z is oxygen and whereinR₁ is selected from the group consisting of hydrogen, halogen, nitro,trifluoromethyl, or lower alkyl, i.e., compounds of the formula ##STR5##wherein R₁ ' is selected from the group consisting of hydrogen, halogen,nitro, trifluoromethyl, and lower alkyl; A, n, and R₃ -R₅ are asdescribed above.

A further preferred embodiment of the present invention encompasses thecompounds of formula I wherein the hetero atom Z is oxygen, R₁ ishydrogen or halogen, with chlorine being the preferred halogen, and isjoined to the benzodiazepine moiety at the 7-position thereof; R₃ ishydrogen; R₄ is hydrogen, lower alkyl, most preferably methyl, orchloromethyl; and R₅ is phenyl or phenyl substituted at the orthoposition with halogen, with fluorine being the most preferred halogen;i.e. compounds of the formula ##STR6## wherein R₁ " is hydrogen orhalogen; A and n are as described above; R₄ ' is hydrogen, lower alkyl,or chloromethyl; and R₇ is hydrogen or halogen.

Most preferred among the compounds of formula I above are those whereinthe hetero atom Z is oxygen; n is 1; R₁ is chlorine and is joined to thebenzodiazepine moiety at the 7-position thereof; R₃ is hydrogen; R₄ ishydrogen, methyl or chloromethyl; and R₅ is phenyl or phenyl substitutedin the ortho position with fluorine.

Another particular aspect of the present invention relates to compoundsof formula I above wherein Z is ##STR7## where R₆ is hydrogen, loweralkyl or acyl, i.e., compounds of the formula ##STR8## wherein A, n, R₁,and R₃ -R₆ are as described above.

Still another particular aspect of the present invention relates tocompounds of formula I above wherein A represents the group --CH₂ --,i.e., compounds of the formula ##STR9## wherein Z, n, R₁, and R₃ -R₅ areas described above.

Yet another particular aspect of the present invention relates tocompounds of formula I above wherein A represents the group ##STR10## Zis oxygen, and n, R₁, R₃, R₄, and R₅ are as described above; or A is##STR11## Z is oxygen, R₄ is the group --CH₂ X where X is chlorine,bromine, lower alkoxy-lower alkyl or di-lower alkylamino and R₁, R₃, R₅,and n are as described above; or A is ##STR12## Z is oxygen, R₅ ispyridyl, and R₁, R₃, R₄ and n are as described above.

Compounds of formula I above wherein the hetero atom Z is oxygen and nis 1 are conveniently prepared by reacting a 4,5-unsaturated1,4-benzodiazepine of the following formula ##STR13## wherein R₁, R₃, R₅and A are as described above and R₂₀ is hydrogen or hydroxy-lower alkyl

with an epoxide compound of the formula ##STR14## wherein R₄ is asdescribed above in the presence of an acidic agent, such as, forexample, an aprotic acid, e.g., aluminum chloride, stannic chloride,zinc chloride, titanium tetrachloride, boron trifluoride, etc.; orp-toluene sulfonic acid, benzene sulfonic acid, and the like. The mostpreferred acidic agents for the purposes of this invention are aluminumchloride and stannic chloride. Examples of compounds of formula IIIuseful in this invention include ethylene oxide, 1,2-propylene oxide,1-chloro-2,3-epoxy propane, etc.

The reaction whereby compounds of formula I above wherein Z is oxygenand n is 1 are prepared from the compounds of formulae II and III isconveniently conducted in the presence of an anhydrous inert organicsolvent. Suitable inert organic solvents for this purpose include, forexample, aromatic hydrocarbons such as benzene, toluene, xylene, etc.;ethers, such as tetrahydrofuran and diethyl ether, or carbon di-sulfide.This reaction may be carried out at a temperature in the range of fromabout -10° to the reflux temperature of the reaction medium, mostpreferably from 10° to the reflux temperature. The selection oftemperature is not critical for the purpose of the present invention andwill, of course, depend upon the characteristics of the compoundsselected as reagents, the solvent medium employed and the nature of theacidic agent used.

The compounds of formula II above are known or can be prepared inanalogy to the preparation of the known compounds.

It should be noted that compounds of formula III above may, in additionto forming the heterocyclic ring between the 4 and 5 positions of thebenzodiazepine moiety upon reaction with the compound of formula II,also react with the nitrogen atom in the 1-position of the compounds offormula II when the nitrogen is unprotected, that is when R₂₀ ishydrogen. Thus, the reaction of a compound of formula II wherein R₂₀ ishydrogen with a compound of formula III can result in a mixture ofcompounds, the first showing no substitution on the 1-nitrogen and thesecond showing hydroxy-lower alkyl substitution of the 1-nitrogen. Forexample, if a compound of formula II wherein R₂₀ is hydrogen is reactedwith a compound of formula III wherein R₄ is hydrogen, i.e. ethyleneoxide, one is able to isolate from the reaction mixture both thecorresponding tricyclic compound wherein the 1-nitrogen is unsubstitutedand the corresponding compound of formula I above wherein the 1-nitrogenis substituted with a β-hydroxy ethyl group. By controlling the reactionconditions there can be obtained high yields of the desired compounds offormula I wherein the 1-nitrogen bears a hydroxy-lower alkylsubstituent. Thus, for example, if the reaction is conducted using anexcess of the compound of formula III, the desired compound of formula Ican be obtained in high yields. Likewise, the choice of the aprotic acidused as the catalyst will also control the yields obtained. Thus,aluminum chloride and stannic chloride are the preferred acid catalystsbecause they promote the production of the desired compounds of formulaI above in high yield. In the most preferred embodiment of the presentinvention, aluminum chloride is used as the acid catalyst.

It would appear that when a compound of formula III is reacted with acompound of formula II, the R₄ bearing carbon atom can be attachedrelative to the benzodiazepine ring in one of two alternate positions,depending upon the point where the epoxide ring cleaves during thereaction. However, experimentation has shown that the epoxide ringevidences a propensity to favor cleavage between the oxygen and theunsubstituted carbon atom. Thus, when cleavage occurs at this point, thecarbon atom bearing the R₄ substituent is bonded to the oxygen atom inthe heterocyclic ring.

Thus, the reaction between the compounds of formulae II and III asdescribed above produces the compounds of Formula I wherein Z is oxygen,n is 1, and the R₄ substituent is joined to the 2-position of theheterocyclic ring, i.e., compounds of the formula ##STR15## wherein R₁,R₃ -R₅ and A are as described above.

In a further process aspect of the present invention, compounds offormula I above are conveniently prepared by reacting a corresponding2-substituted aminophenyl ketone of the formula ##STR16## wherein R₁,R₃, R₅ and A are as described above, X' is chlorine, bromine or iodineand R₂₁ is hydrogen or the group --(CH₂)_(m) --OR₂₂ wherein m is aninteger from 1-7 and R₂₂ is any suitable protecting group

with a diamine or aminoalkanol of the general formula ##STR17## whereinR₄, n and Z are as described above.

The reaction between the compounds of formulae IV and V above isconducted in a reaction medium containing a base and an inert organicsolvent at a temperature in the range of from about 25° C. to the refluxtemperature of the reaction medium, preferably at about the refluxtemperature. Suitable bases for the purposes of this invention areinorganic bases, such as sodium acetate, and organic bases such as thetertiary amines, for example, trialkylamines, with triethylamine andpyridine being preferred. A variety of organic solvents are useful forthe purposes of this invention. Among these suitable solvents arearomatic hydrocarbons, such as benzene, toluene, xylene, etc.; highboiling ethers, such as tetrahydrofuran and dioxane; and amides, such asdimethylformamide, diethylformamide and the like. Examples of compoundsof formula V useful in this invention include 2-aminoethanol,ethylene-diamine, 3-aminopropanol, etc.

The compounds of formulae IV and V above are readily prepared in amanner known in the art. It should be noted that in preparing thecompounds of formula IV above wherein R₂₁ is the group --(CH₂)_(m)--OR₂₂, i.e. in preparing compounds of the formula ##STR18## wherein R₁,R₃, R₅, R₂₂, m and X' are as described above

it is expedient to first protect the hydroxyl group of the hydroxy-loweralkyl substituent present in the ketone starting material beforeintroducing the ##STR19## substitient, A, R₃ and X' being defined asabove, into the molecule. By so-protecting the hydroxyl group with theprotecting group identified above as R₂₂ one can avoid unwanted sidereactions and unwanted side products which of necessity render thereaction less efficient. Suitable protecting groups for this purposeinclude the acyl moiety of a lower alkanoic acid such as acetyl,propionyl and the like and carbobenzoxy. Following preparation of theformula IV compound and completion of the reaction between the compoundsof Formulae IV and V above, the protecting group can then be split off.The splitting off of the protecting group can be effected byconventional techniques, for example, by alkaline hydrolysis. Thisalkaline hydrolysis is expediently carried out in the presence of aninert solvent. Suitable bases include alkali-hydroxides or alkalineearth metal hydroxides, such as sodium hydroxide, calcium hydroxide andthe like.

If, in the compounds of formula IV, X' is chlorine or bromine, thereaction mixture may also contain sodium iodide in order to exchange theX' substituent for the more reactive iodine atom which then is removedin the ensuing reaction.

The compounds of formula I wherein the hetero atom Z is ##STR20## and R₆is lower alkyl or acyl are prepared from the corresponding compounds offormula I wherein Z is ##STR21## and R₆ is hydrogen by conventionalalkylation or acylation procedures. By controlling the reactionconditions alkylation or acylation can be accomplished on the nitrogenof the heterocyclic ring without affecting other vulnerable positions onthe benzodiazepine moiety.

The reaction path described above for the cyclization process to preparecompounds of formula I is believed to proceed via an intermediate of thefollowing proposed structure ##STR22## wherein R, R₃ -R₅, R₂₁, A, Z andn are as described above which need not be isolated from the reactionmixture as it cyclizes to the desired compounds of formula I under thereaction conditions employed. By using less energetic reactionconditions, the compounds of the formula VI can be isolated andsubsequently cyclized to the desired product. However, in a preferredembodiment, the intermediate is not isolated but is permitted to cyclizein the reaction medium in which it is prepared.

In a further process aspect of the present invention, the hydroxy-loweralkyl group in the 1-position of the compounds of formula I above can beintroduced onto the 1-nitrogen after formation of the tricycliccompounds. For example, if the R₂₀ substituent in a compound of formulaII is hydrogen, the reaction of said compound with a compound of formulaIII may produce the corresponding tricyclic compound wherein the1-nitrogen is unsubstituted. Further, if the R₂₁ substitient in acompound of formula IV is hydrogen, reaction of this compound with acompound of formula V and cyclization of the resulting intermediate willproduce the corresponding tricyclic compound wherein the 1-nitrogen isunsubstituted. In either case, the desired compound of formula I abovecan be prepared by introducing the hydroxy-lower alkyl group into themolecule after formation of the tricyclic compound. The hydroxy-loweralkyl group can be introduced into the 1-unsubstituted tricycliccompound by reacting said compound with a suitable alkylating agent.Thus, one can prepare a compound of formula I above by first preparingthe 1-sodio derivative of a compound of the formula ##STR23## whereinR₁, R₃ -R₅, A, Z and n are as described above and without isolationreacting said 1-sodio derivative with a suitable alkylating agent suchas a halo-lower alkanol. Representative of such alkylating agents are2-bromoethanol, 3-bromopropanol and the like.

The 1-sodio derivative of a compound of formula I-f above can beprepared by treating said compound with a sodium lower alkoxide, such assodium methoxide or with sodium hydride. This reaction is expedientlyeffected in the presence of an inert organic solvent such asdimethylformamide (DMF), aromatic hydrocarbons, i.e. benzene, tolueneand the like, with DMF being the preferred solvent. For the purposes ofthis reaction, temperatures above and below room temperature may beemployed. In a preferred embodiment temperatures between about 0° and10° C. are utilized.

The alkylation of the 1-sodio derivative of a compound of formula I-fabove is expediently effected in the presence of an inert solvent suchas DMF, aromatic hydrocarbons, i.e., benzene, toluene and the like, withDMF being the preferred solvent. This alkylation reaction may beeffected using temperatures above and below room temperature, withtemperatures between about 50° C. and room temperature being preferred.

In a further process aspect of the present invention, a compound offormula I above wherein R₁ is halogen i.e., a compound of the formula##STR24## wherein R₃ -R₅, A, Z and n are as described above may beprepared by reacting the 1-sodio derivative of a compound of the formula##STR25## wherein R₃ -R₅, A, Z and n are as described above with acompound of the formula

    X--(CH.sub.2).sub.m COO--lower alkyl                       VII

wherein X is a halogen atom selected from the group consisting ofchlorine, bromine and iodine and m is a whole integer from 1-7

and without isolation, reducing the ester derivatives so-obtained with asuitable reducing agent such as lithium aluminum hydride.

Representative of the compounds of formula VII suitable for the processare ethyl bromoacetate, ethyl 3-bromopropionate, and the like. The1-sodio derivative of the compound of formula I-h can be prepared, asdescribed hereinbefore. The alkylation reaction is expediently effectedin the presence of an inert solvent such as DMF.

The tricyclic benzodiazepine derivatives of formula I above are usefulas pharamceuticals and are characterized by activity as sedative, musclerelaxant and anti-convulsant agents. These compounds can be used in theform of conventional pharmaceutical preparations; for example, theaforesaid compounds can be mixed with conventional organic or inorganic,inert pharamceutical carriers suitable for parenteral or enteraladministration such as for example, water gelatin, lactose, starch,magnesium stearate, talc, vegetable oil, gums, polyalkylene glycols,Vaseline or the like. They can be administered in conventionalpharmaceutical forms, e.g., solid forms, for example, tablets, dragees,capsules, suppositories or the like, or in liquid forms, for example,solutions, suspensions or emulsions. Moreover, the pharmaceuticalcompositions containing compounds of this invention can be subjected toconventional pharmaceutical expedients such as sterilization, and cancontain conventional pharmaceutical excipients such as preservations,stabilizing agents, wetting agents, emulsifying agents, salts for theadjustment of osmotic pressure, or buffers. The compositions can alsocontain other therapeutically active materials.

A suitable pharamceutical dosage unit can contain from about 1 to about500 mg of the aforesaid compounds of formula I; with a dosage range offrom about 1 mg to about 100 mg being the preferred oral administrationand a dosage range of from about 1 mg to about 50 mg being preferred forpatenteral administration. However, for any particular subject, thespecific dosage regimen should be adjusted according to individual needand the professional judgment of the person administering or supervisingthe administration of the aforesaid compounds. It is to be understoodthat the dosages set forth herein are exemplary only and that they donot, to any extent, limit the scope or practice of this invention.

The term "dosage unit" as employed throughout this specification refersto pharmaceutically discrete units suitable as unitary dosages formammalian subjects each containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical diluent, carrier orvehicle.

The following examples are illustrative, but not limitative of thisinvention. All temperatures given are in degrees centigrade, unlessindicated otherwise.

EXAMPLE 1 Preparation of10-chloro-2,3,5-11b-tetrahydro-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(7H)-one ##STR26##

To 5 gm. (18.5 mmole) of7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 90 ml. ofdry benzene was added 5.0 g. (37 mmole) of aluminum chloride. Thereaction mixture was stirred 6 hours at reflux, cooled to roomtemperature and treated with 4.4 g. (0.1 mole) of ethylene oxide. Thereaction mixture was stirred 18 hours, the benzene was then removed andthe residue was treated with aqueous ammonium hydroxide and 100 ml. ofmethylene chloride. The resulting precipitate was removed by filtration.The organic layer was then separated, washed with brine, dried and thesolvent evaporated to yield a residue which was crystallized from etherand recrystallized from methylene chloride-hexane to give theabove-titled product as colorless prisms, m.p. 125°-135° and thenresetting, m.p. 173°-177°.

EXAMPLE 2 Preparation of10-chloro-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydro-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(7H)-one ##STR27##

The filtrates from Example 1 above were dissolved in methylene chlorideand chromatographed over silica gel (200 g.) with methylene chloride(300 ml.) and with 700 ml. of ethyl acetate. The ethyl acetate fractionwas evaporated to dryness and crystallized from ether. Recrystallizationfrom methylene chloride-hexane gave the above-titled product ascolorless prisms, m.p. 134°-137°.

EXAMPLE 3

Preparation of10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydroxazolo[3,2-d][1,4]benzodiazepin-6-(7H)-one##STR28##

To 15 g. (51.9 mmole) of7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in150 ml. of dry benzene, 9 g. (67.7 mmole) of aluminum chloride was addedand stirring was continued 15 minutes. The reaction mixture was cooledin an ice bath and 8.8 g. (0.2 mole) of ethylene oxide was addeddropwise. After 18 hours of stirring at room temperature, the reactionmixture was heated to 40° for 1 hour and then cooled to room temperatureand treated with 5 g. (37.6 mmole) of aluminum chloride, followed by 4.4g. (0.1 mole) of ethylene oxide. The reaction mixture was heated 4 hoursat 45°-50° and then evaporated to dryness. Methylene chloride, ice andammonium hydroxide were added and the solid removed by filtration. Thefiltrate was separated and the organic phase reduced to dryness invacuo. The residue was dissolved in dilute hydrochloric acid and the pHof the solution adjusted to 5 with ammonium hydoxide. The acidicsolution was washed with ether, made basic and extracted with methylenechloride. The organic phase was washed with brine, dried and evaporatedto dryness. Recrystallization from methylene chloride-hexane gave theabove-titled product as colorless rods, m.p. 183°-184°.

EXAMPLE 4 Preparation of10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one##STR29##

The ether wash in Example 3 of the said solution at pH 5 was evaporatedto dryness, dissolved in methylene chloride and chromatographed over 200g. of silica gel with methylene chloride and ethyl acetate whichfractions were combined and the solvents removed to give crude product.Recrystallizations from methylene chloride petroleum ether gave theabove-titled product as colorless plates, m.p. 147°-151°.

EXAMPLE 5 Preparation of10-chloro-7-methyl-2,3,5,11b-tetrahydro-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(7H)-one##STR30## Method A

A mixture of 100 ml. of dried benzene and 5.0 g. of aluminum chlorideunder a dry ice-acetone filled condenser was stirred and treated with10.0 g. (35 mmole) of7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one givinga yellow solid. Stirring was continued for 20 minutes and after theaddition of 35 ml. of hexane, the mixture was cooled in an ice-bath.Upon the addition of 7 ml. of ethylene oxide, the yellow soliddissolved. The reaction mixture was warmed to room temperature and wasstirred overnight. The benzene solution was repartitioned betweenmethylene chloride and iced aqueous ammonium hydroxide. Filtrationremoved a large portion of the aluminum salts and the organic layer wasseparated, washed with water, dried and evaporated. The resultantresidue was washed with ether to give the above-titled product ascolorless crystals, m.p. 179°-184°. Two recrystallizations frommethylene chloride-hexane gave colorless rods, m.p. 182°-184°.

Method B

A solution of 6.4 g. (20 mmole) of2-(2-chloro-N-methylacetamido)-5-chlorobenzophenone, 12.2 g. (200 mmole)of 2-aminoethanol, 50 ml. of triethylamine and 300 ml. of ethanol wasstirred overnight at reflux. The reaction mixture was concentrated to asemi-solid residue, from which the above-titled product was obtained asan ether insoluble crystalline material, m.p. 180°-183°.

EXAMPLE 6 Preparation of10-chloro-2,7-dimethyl-2,3,5,11b-tetrahydro-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one(2,11b cis) ##STR31##

A mixture of 10.0 g. (35 mmole) of7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 6.7g. of aluminum chloride, 300 ml. of benzene and 30 ml. of hexane waschilled in an ice-bath and was treated with 10 ml. of propylene oxide.The reaction mixture was warmed to room temperature and was stirredovernight. Work-up as in Method A, Example 5, yielded a mixture of theepimers of10-chloro-2,7-dimethyl-2,3,5,11b-tetrahydro-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one.A solution of 1.0 g. of this mixture was stirred overnight at 80° in 25ml. of boron trifluoride etherate. The reaction mixture was pouredcarefully into ice water and made basic with ammonium hydroxide. Themixture was extracted with chloroform, water-washed, dried andconcentrated to a solid residue. Three recrytallizations from methylenechloride-hexane gave the above-titled isomer, m.p. 142°-143°.

EXAMPLE 7 Preparation of10-chloro-2-chloromethyl-2,3,5,11b-tetrahydro-7-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one##STR32##

A mixture of 10 g. (35 mmole) of7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 10 g.of aluminum chloride, and 200 ml. of dried benzene was treated with 30ml. of 1-chloro-2,3-epoxypropane in 100 ml. of benzene. The reactionmixture was stirred overnight. Work-up as in Method A, Example 5, abovegave 32 g. of a crude oil. The oil was dissolved in benzene, filteredover Florisil, evaporated to dryness and crystallized fromether-petroleum ether to give the above-titled product as colorlessneedles, m.p. 140°-142°.

EXAMPLE 8 Preparation of10-chloro-7-methyl-2,3,5,6,7,11b-hexahydro-11b-phenyloxazolo[3,2-d][1,4]benzodiazepine##STR33## Method A

A mixture of 12.5 g. (46 mmole) of7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepinehydrochloride, 5.0 g. of aluminum chloride, 200 ml. of benzene and 30ml. of hexane was stirred for 20 minutes, chilled in an ice-bath andthen treated with 7.0 ml. of ethylene oxide. The reaction mixture waswarmed to room temperature and stirred overnight. The benzene wasremoved by evaporation and the residue was partitioned between methylenechloride and dilute ammonium hydroxide. The solid was removed byfiltration and the organic layer washed with water, dried and evaporatedto give an orange oil. Upon standing, the oil crystallized and theresultant solid was recrystallized from hexane to give the above-titledproduct. An analytical sample was obtained as colorless prisms, m.p.109°-110°, by recrystallization from ether.

Method B

A solution of 5.6 g. (18.2 mmole) of5-chloro-2-(2-chloroethylmethylamino)benzophenone, 5.0 g. ofsodium-iodide, 50 ml. of 2-aminoethanol, 50 ml. of triethylamine and 100ml. of ethanol was heated at reflux for 17 hours. The reaction mixturewas poured into ice water and was extracted with methylene chloride. Theorganic phase was washed with water, dried and evaporated to an oil. Theoil was cooked out with petroleum ether and the above-titled productcrystallized from the solvent, m.p. 107°-109°.

EXAMPLE 9 Preparation of10-chloro-1,2,3,5,7,11b-hexahydro-7-methyl-11b-phenyl-6H-imidazo[1,2-d][1,4]benzodiazepin-6-one##STR34##

A solution of 6.4 g. (20 mmole) of2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone, 12.0 g. (0.2 mole)of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol washeated at reflux for 20 hours. The reaction mixture was concentrated toa residue which was partitioned between ether and water. The ether layerwas washed with water, dried and concentrated to a small amount ofliquid which was treated with a small amount of ethanol to give uponstanding the above-titled product as colorless crystals, m.p. 164°-167°.

EXAMPLE 10 Preparation of11-chloro-3,4,6,7,8,12b-hexahydro-8-methyl-12b-phenyl-2H-[1,3]oxazino[3,2-d][1,4]benzodiazepine##STR35##

A solution of 5.0 g. (16 mmole) of5-chloro-2-(2-chloroethylmethylamino)benzophenone, 3.75 g. (50 mmole) of3-aminopropanol, 50 ml. of triethylamine and 250 ml. of ethanol wasstirred at reflux for 48 hours. The reaction mixture was then evaporatedto a residue which was washed with water, dissolved in methylenechloride and chromatographed over a column of Florisil. The firstfraction yielded the recovery of 2.7 g. of starting material. Elutionwith acetone, ethanol, methanol and finally with ammonial methanol gavea compound of very low Rf on fluorescent silica eluted with ethanol.Crystallization from acetone and recrystallizations from ether-petroleumether gave the above-titled product as colorless prisms, m.p. 142°-144°.

EXAMPLE 11 Preparation of10-chloro-2,3,5,6,7,11b-hexahydro-7-methyl-11b-phenyl-1H-imidazo[1,2-d][1,4]benzodiazepine##STR36##

A solution of 5.0 g. (16 mmole) of5-chloro-2-(2-chloroethylmethylamino)benzophenone, 3.0 g. (50 mmole) ofethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol wasstirred at reflux for 48 hours. The solvents were removed by evaporationand the residue containing starting material and the product was washedwith water, chromatographed over Florisil, and recrystallized frompetroleum ether to give the above-titled product as yellow prisms, m.p.100°-102°.

EXAMPLE 12 Preparation of10-chloro-2,3,5,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one(2,11b trans)

A solution of 67 g. (0.19 mole) of2-(2-bromoacetamido)-5-chloro-benzophenone, 500 ml. of xylene, 15.7 g.(0.21 mole) of 1-amino-2-propanol and 25 ml. of triethylamine wasstirred at reflux for 20 hours. The reaction mixture was concentrated invacuo to a residue which was partitioned between methylene chloride andwater. The organic layer was washed with water, dried and concentratedto an oil which was crystallized from ethyl acetate to give 18.3 g. of acolorless solid, m.p. 181°-184°. Thin layer chromatography on Eastmanalumina plates with an eluant of 3 parts of hexane and 2 parts of ethylacetate revealed the presence of two compounds. The product wasdissolved in chloroform and chromatographed over Woelm neutral aluminaI. A mixture concentrated in the above-titled product (the faster of thetwo compounds) was collected in 30% ethyl acetate-70% hexane.Recrystallizations from methylene chloride gave colorless prisms, m.p.188°-189°.

EXAMPLE 13 Preparation of 10-chloro-2,3,5,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one(2,11b cis)

A 1.0 g. sample (0.3 mmol) of the two-compound mixture obtained inExample 12 was stirred 17 hours at 80° in a solution with 25 ml. ofboron trifluoride etherate. The reaction mixture was poured over 200 g.of ice and was carefully treated with ammonium hydroxide to give a pH of8. The resultant solid was removed by filtration and was air dried togive the above-titled product. Two recrystallizations fromchloroform-hexane gave colorless prisms, m.p. 172°-174°.

EXAMPLE 14 Preparation of a mixture of10-chloro-2,3,5,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one(2,11b cis) and10-chloro-2,3,5,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one(2,11b trans) Method A

To a solution of 35.26 g. (0.1 mole) of2-(2-bromoacetamido)-5-chlorobenzophenone, 100 ml. of triethylamine and600 ml. of ethanol, 22.5 g. (0.3 mole) of 1-amino-2-propanol was added.The reaction mixture was stirred at room temperature for 65 hours. Thesolvent was removed in vacuo and the residue partitioned between waterand ethyl acetate. The organic layer was dried and concentrated to givea colorless oil. An ether solution of the oil was treated with dryhydrogen chloride to form the hydrochloride salt which wasrecrystallized from ethanol to give colorless prisms of5-chloro-2[2-(2-hydroxypropylamino)acetamido]benzophenone, m.p.194°-195°.

A pyridine solution of 8.0 g. (23 mmol) of5-chloro-2[2-(2-hydroxypropylamino)acetamido]benzophenone was stirred 17hours at reflux in the presence of 0.5 g. of pyridine hydrochloride. Thereaction mixture was concentrated in vacuo to a residue which wascrystallized from ethanol as colorless crystals, m.p. 184°-185°. Theproduct is a mixture of the above-titled compounds in about equalportions.

In a similar fashion,5-chloro-2[2-(2-hydroxypropylamino)acetamido]benzophenone could bedehydrated to give a mixture of the same two compounds by heating atreflux 72 hours in ethanol or by heating 65 hours at reflux in xylene.

Method B

A solution of 5.4 g. (20 mmol) of7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and 20 mmol ofstannic chloride in 300 ml. of dry benzene was treated with 60 mmol ofpropylene oxide and stirred under dry nitrogen for 22 hours at 80°. Thereaction mixture was concentrated in vacuo to a residue which waspartitioned between methylene chloride and ammonia. The organic phasewas washed with water, dried and concentrated to give a crystallineresidue. Recrystallization from ethyl acetate gave colorless prisms,m.p. 178°-183°, of a mixture of the above-titled compounds.

Similarly, this reaction was effected in benzene solution using aluminumtrichloride, titanium tetrachloride or boron trifluoride etherate ascatalysts.

Method C

Following the procedures set forth in Examples 12 and 13, the mixturesobtained in Methods A and B can be separated in order to isolate10-chloro-2,3,5,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one(2,11b cis) and10-chloro-2,3,5,11b-tetrahydro-2-methyl-11b-phenyloxazolo-[3,2-d][1,4]benzodiazepin-6(7H)-one(2,11b trans).

EXAMPLE 15 Preparation of10-chloro-2,3,5,11b-tetrahydro-3-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one(3,11b cis)

A mixture of 79.4 g. (225 mmole) of2-(2-bromoacetamido)-5-chlorobenzophenone, 25 g. of 2-aminopropanolhydrochloride, 95 ml. of triethylamine and 500 ml. of ethanol wasstirred overnight at room temperature, and then at reflux for 5 hours.The solution was concentrated under reduced pressure to a residue whichwas partitioned between ether and water. The organic layer was washedwith water, dried and treated with hydrogen chloride to give 18 g. of acolorless solid. Recrystallizations from ethanol-ether gave prisms of5-chloro-2-[2-(1-hydroxy-2-propylamino)acetimido]-benzophenone,hydrochloride, m.p. 183°-186°.

A solution of 5 g. (13 mmol) of the free base5-chloro-2[1-hydroxy-2-propylamino)acetamido]benzophenone was heated 16hours in refluxing pyridine (100 ml.). The solution was concentrated invacuo to an oil which was chromatographed over silica. The firstmaterial taken in 60% ethyl acetate, 40% hexane was2-amino-5-chlorobenzophenone. The next material eluted was combined togive10-chloro-2,3,5,11b-tetrahydro-3-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one(3,11b cis) which was recrystallized 3 times to give colorless prisms,m.p. 88°-96°. Sublimation under reduced pressure gave a colorless solid,m.p. 84°-98°.

EXAMPLE 16 Preparation of10-chloro-11b-(2-chlorophenyl)-2,3,5,11b-tetrahydrooxazlo[3,2-d][1,4]benzodiazepin-6(7H)-one

A suspension of 4.3 g. (0.0328 M) of aluminum chloride in 200 ml. of drybenzene under nitrogen was treated with 5.0 g. (0.0164 M) of7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one andthe mixture was stirred in an ice bath for 20 min. when 2.2 g. (0.0492M) of ethylene oxide was added and after 18 hr. at room temperature, anadditional 2.2 g. of ethylene oxide was added. After 3 hr., the mixturewas heated under reflux for 10 min., then evaporated to dryness.

The residue was made basic with ammonium hydroxide, dichloromethane (100ml.) was added and the mixture was filtered. The organic layer wasseparated, washed with saturated brine, dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was crystallized fromether and recrystallized from a mixture of dichloromethane and petroleumether to give10-chloro-11b-(2-chlorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one as white prisms, m.p. 213°-216°.

EXAMPLE 17 Preparation of10-chloro-11b-(2-chlorophenyl-7-methoxymethyl-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one

A solution of 2.8 g. of10-chloro-11b-(2-chlorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 50 ml. of dimethylformamide was cooledto -10° and treated with 0.65 g. of sodium methoxide. After stirring for5 minutes, the mixture was cooled to -40° and 1 ml. of chlorodimethylether was added. The cooling bath was removed and when the temperaturehad reached 0° the reaction mixture was poured into 300 ml. ofice-water. The precipitated material was collected by suction anddissolved in methylene chloride. The solution was dried over sodiumsulfate, filtered and evaporated. The residue was crystallized from amixture of ether and hexane to give, after recyrstallization fromethanol,10-chloro-11b-(2-chlorophenyl)-7-methoxymethyl-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4] benzodiazepin-6(7H)-one as white prisms, m.p. 144°-147°.

EXAMPLE 18 Preparation of Ethyl7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-3-carboxylate

A solution of 50 g. of sodium nitrite is added dropwise to a solution of34.6 g. of ethyl 2'-benzoyl-4'-chloro-malonanilate in 250 ml. of glacialacetic acid. After 11/2 hours stirring at room temperature, the oximecrystallizes out and is filtered off by suction, washed with water anddried in vacuum. Ethyl 2'-benzoyl-4'-chloro-mesoxalanilate 2-oxime, m.p.98°-105° is obtained.

Water is added dropwise to the filtrate with stirring whereby furtheroxime crystallizes out.

According to thin layer chromatogram, the crude product consists of amixture of the two stereoisomeric oximes. These may be separated bychromatography on Kieselgel with 20% acetic ester in methylene chloride.The first eluted isomer melts at 115°-117° after crystallization fromalcohol-water. The oxime eluted later shows a m.p. of 131°-132° aftercrystallization from ether-hexane.

A solution of 2 g. of ethyl 2'-benzoyl-4'-chloro-mesoxalanilate 2-oximein 40 ml. of methylene chloride is treated with 2 g. of zinc dust. 4 ml.of glacial acetic acid are added dropwise within 5 minutes withstirring. After the addition, the mixture is stirred at room temperaturefor 1 hour. The reaction mixture is filtered and the filtrateevaporated. The residue is boiled under reflux for 2 hours in 20 ml. ofbenzene and 2 ml. of glacial acetic acid. The reaction mixture is washedout with 10% soda solution, dried over sodium sulphate and evaporated.Crystallization of the residue from alcohol yields ethyl7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-3-carboxylate,m.p. 232°-234°. Further material crystallizes from the mother liquor.

EXAMPLE 19 Preparation of10-chloro-11b-phenyl-2,3,5,11b-tetrahydrooxazolo [3,2-d][1,4]benzodiazepin-6(7H)-one-5-carboxylic acid ethyl ester

To a solution of 3.1 g. (0.0118 M) of stannic chloride in 35 ml of dryethylene dichloride under nitrogen was added 1.5 g. (0.00438 M) of7-chloro-1,3-dihydro-2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-carboxylicacid ethyl ester. The reaction was stirred in an ice bath, when asolution of 1.0 g. (0.0233 M) of ethylene oxide in 5 ml. of ethylenedichloride was added. The mixture was stirred at room temperature for 3hr. and then made basic with mixture of ammonium hydroxide and ice. Themixture was filtered, and the filtrate was dried with anhydrous sodiumsulfate and evaporated to dryness. The residue was crystallized fromether. Recrystallization from a mixture of dichloromethane and petroleumether gave 10-chloro-11b-phenyl-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one-5-carboxylic acid ethyl ester as whiterods, m.p. 205°-207°.

EXAMPLE 20 Preparation of10-Chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-oneMethod A

A solution of 3.3 g (0.01 M) of7-chloro-1-(2-hydroxyethyl)-5-(2-fluorophenyl01,3-dihydro-2H-1,4-benzodiazepin-2-onein 40 ml of 1,2-dichloro ethane under nitrogen was treated with 5.2 g(0.02 M) of stannic chloride with stirring. After 20 min, the mixturewas cooled in an ice bath and 2.6 g (0.06 M) of ethylene oxide wasadded. After 1 hr at room temperature, the reaction mixture was madebasic with ammonium hydroxide and filtered. The precipitate was washedwith dichloromethane, and the combined filtrates were separated. Theorganic layer was washed with 40 ml of dilute ammonium hydroxide, driedover anhydrous sodium sulfate and evaporated to dryness. The residue wascrystallized from a mixture of ether and petroleum ether andrecrystallized from toluene to give the above named product as whiteprisms, mp 142°-147°.

Method B

A solution of 5 g (0.015 M) of10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-onein 50 ml of dry N,N-dimethylformamide under nitrogen was treated with1.3 g (0.030 M) of a 57% dispersion of sodium hydride in mineral oil andafter 30 min, 4.0 g (0.030 M) of 2-bromoethanol was added. The mixturewas kept at 60° for 18 hrs, when 450 ml of water was added, followed byenough 3N hydrochloric acid to lower pH to less than 5. The mixture wasextracted with dichloromethane (3 × 125 ml). The organic layers werecombined, washed with saturated brine, dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was dissolved in ether(50 ml) and filtered through 75 g of neutral alumina. Elution with ethylacetate and methanol gave the above named product, which wascrystallized from ether to give the product as white prisms, mp142°-147°.

EXAMPLE 21 Preparation of11b-(2-Fluorophenyl)-2,3,5-11b-tetrahydro-10-iodo-oxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one

To a mixture of 5.34 g (40 mmole) of aluminum chloride and 250 ml ofbenzene was added 7.6 g (20 mmole) of5-(2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one. Thismixture was then cooled in an ice bath, 10 ml (0.2 mole) of ethyleneoxide was added to it and then it was stirred for 2 days at roomtemperature. The mixture was concentrated in vacuo and the residueshaken with methylene chloride and saturated sodium bicarbonatesolution. The insoluble material was filtered off and discarded. Themethylene chloride layer was separated, dried over sodium sulfate andconcentrated in vacuo. The residue was crystallized with ether to givethe above named product, mp 180°-184°. Recrystallization from 70%aqueous ethanol gave colorless needles, mp 193°-196°.

EXAMPLE 22 Preparation of11b-(2-Fluorophenyl)-7-(2-hydroxyethyl)-10-iodo-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one

A solution of 0.8 g (0.00187 M) of11b-(2-fluorophenyl)-2,3,5-11b-tetrahydro-10-iodo-oxazolo[3,2-d][1,4]benzodiazepin-6(7H)-onein 25 ml of dry N,N-dimethylformamide under nitrogen was treated with0.11 g (0.00262 M) of a 57% dispersion of sodium hydride in mineral oil.After stirring for 30 minutes in an ice bath, 0.37 g (0.00374 M) of2-bromoethanol was added, and the reaction was heated to 115°-120° for 3hr and at 125°-130° for 1 hr. The solvent was removed under vacuum, andthe residue was dissolved in 25 ml of dichloromethane and washed withsaturated brine, dried over anhydrous sodium sulfate and evaporated todryness. The residue was heated under reflux for 15 minutes in asolution of 10 ml of triethylamine, containing 0.5 g (0.005 M) ofsuccinic anhydride. Solvent was removed under reduced pressure and theresidue was dissolved in 25 ml of dichloromethane. The half ester wasextracted into 20 ml of dilute ammonium hydroxide which was then treatedwith 5 ml of 3N sodium hydroxide for 1 hr. The solution was extractedwith 25 ml of dichloromethane, which was dried with anhydrous sodiumsulfate, and evaporated. The resulting oil was crystallized from etherto give the above named product as white plates, mp 160°-165°.

EXAMPLE 23 Preparation of11b-(2-Chlorophenyl)-10-nitro-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]-benzodiazepin-6(7H)-one

A solution of 5.2 g (0.02 M) of stannic chloride in 60 ml of dryethylene dichloride under nitrogen was treated with 2.9 g (0.0091 M) of5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. Thereaction was cooled in an ice bath, and 2.6 g (0.06 M) of ethylene oxidein 10 ml of ethylene dichloride was added with stirring over an 8 minperiod. After 18 hr at room temperature, the solution was made basicwith concentrated ammonium hydroxide and filtered. The filtrates werewashed with a saturated solution of brine, dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was crystallized from amixture of dichloromethane, methanol and petroleum ether to give theabove named product as white rods, melting at 201°-203°.

EXAMPLE 24 Preparation of11b-(2-Chlorophenyl)-7-(2-hydroxyethyl)-10-nitro-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one

A solution of 1.5 g (0.0041 M) of11b-(2-chlorophenyl)-10-nitro-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-onein 30 ml of dry N,N-dimethylformamide was treated with 0.34 g (0.008 M)of a 57% dispersion of sodium hydride in mineral oil with stirring undernitrogen. After 30 min, 1.5 g (0.012 M) of 2-bromoethanol was added andthe reaction was heated to 90° for 3 hr. The solvent was removed undervacuum, and the residue was dissolved in 50 ml of dichloromethane whichwas then washed with 50 ml of water, 25 ml of a saturated solution ofbrine, dried over anhydrous sodium sulfate and evaporated to dryness.The residue was crystallized from ether, and recrystallized from amixture of dichloromethane and methanol to give the product as paleyellow prisms, m.p. 185°-190°(dec.).

EXAMPLE 25

In an analogous manner to the procedures described in Example 24, thefollowing compounds may be prepared using10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-oneas the starting material:

10-Chloro-11b-(2-fluorophenyl)-7-(2-dimethylaminoethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one,from (2-bromoethyl)dimethylamine

10-Chloro-11b-(2-fluorophenyl)-7-(3-aminopropyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)one, from 3-bromopropylamine

10-Chloro-11b(2-fluorophenyl)-7-(3-methylaminopropyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)one,from (3-bromopropyl)methylamine

10-Chloro-11b-(2-fluorophenyl)-7-(2-diethylaminoethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one,from (2-bromoethyl)diethylamine

EXAMPLE 26 Preparation of10-Chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one

A solution of 33.3g (0.1 M) of10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 100 ml of dry N,N-dimethylformamide wastreated with 6.6g (0.138 M) of a 50 percent dispersion of sodium hydridein mineral oil. The mixture was stirred for 0.5 hour at roomtemperature, was then cooled to 5°-10° and treated with a solution of31g (0.186 M) of ethyl bromoacetate in 25 ml of dryN,N-dimethylformamide. The resulting mixture was allowed to stir at roomtemperature for 18 hours when 3 ml of water was carefully added. Thesolution was next evaporated to dryness under reduced pressure. Theresidue was next treated with 50 ml of toluene and evaporated todryness. This procedure was repeated twice in order to azeotrope anyremaining water or N,N-dimethylformamide. The crude ester thus obtainedwas dissolved in 250 ml of dry tetrahydrofuran, cooled to 0° and wastreated by the portionwise addition of 1.9g (0.05 M) of lithiumaluminium hydride. The cooling bath was removed and the mixture wasallowed to stir for 3 hours. Enough saturated sodium bicarbonatesolution was added to coagulate the solids and the mixture was filtered.The filtrates were concentrated to dryness and dissolved indichloromethane. The solution was washed with 1N hydrochloric acid,water, saturated brine, dried over anhydrous sodium sulfate andevaporated. The residue was crystallized from toluene to give the abovenamed product as white prisms, m.p. 142°-147°.

EXAMPLE 27 Preparation of5-Chloro-2-fluoro-2-(2-hydroxyethyl)aminobenzophenone

A solution of 10g (0.04 M) of 2-amino-5-chloro-2'-fluorobenzophenone in100 ml of dry benzene was treated with 10.6g (0.08 M) of aluminiumchloride under nitrogen. The reaction mixture was next treated with 7g(0.16 M) of ethylene oxide (5 minute period), keeping the temperaturebelow 35° with an ice bath. After 65 hours at room temperature, theprocedure was repeated using the same amounts of aluminium chloride andethylene oxide as before. After 5 hours at room temperature, the benzenewas removed by distillation, and the residue was made basic withammonium hydroxide, stirred with 100 ml of dichloromethane and filtered.The organic layer was separated, washed with saturated brine, dried overanhydrous sodium sulfate and evaporated to dryness. The product wasrecrystallized three times from a mixture of ether and petroleum etherto give the above named product as yellow needles, m.p. 96°-101°.

EXAMPLE 28 Preparation of2-(2-Acetoxyethylamino)-5-chloro-2'-fluorobenzophenone

A solution of 15g (0.0516 M) of5-chloro-2-fluoro-2-(2-hydroxyethyl)amino-benzophenone in 75 ml ofacetic anhydride was heated on the steam bath for 1 hour. Solvent wasremoved under reduced pressure and the residue was dissolved in 75 ml ofbenzene. This solution was filtered through a column of 100g of silicagel. The column was eluted with 500 ml of benzene which was discarded,and 1 l. of dichloromethane. Removal of the dichloromethane gave aresidue which was crystallized from a mixture of ether and petroleumether to give the above named product as yellow rods, m.p. 48°-55°.

EXAMPLE 29 Preparation of2-[N-(2-Acetoxyethyl)-N-(2-bromoacetyl)amino]-5-chloro-2'-fluorobenzophenone

A mixture of 2.5g (0.0074 M) of2-(2-acetoxyethylamino)-5-chloro-2'-fluorobenzophenone and 5g (0.0362 M)of potassium carbonate in 25 ml of dry chloroform was treated with 2.0g(0.0096 M) of bromoacetyl bromide over a 20 minute period with stirring.The mixture was stirred for 1 hour at room temperature when 25 ml ofwater was added, and the chloroform layer was separated. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate and evaporated to dryness. The residual oil was dissolved in 10ml of benzene, and chromatographed over 100g of Florisil. Elution with 1l. of benzene gave 0.2g of an oil and elution with 1.5 l. of ether and 1l. of ethyl acetate gave 1.8g and 1.0g, respectively of a colorless oilwhich were combined and recrystallized from a mixture of dichloromethaneand petroleum ether to give the above named product as white prisms,m.p. 84°-88°.

EXAMPLE 30 Preparation of7-(2-Acetoxyethyl)-10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one

A solution containing 1.5g (0.0033 M) of2-[N-(2-acetoxyethyl)-N-(2-bromoacetyl)amino]-5-chloro-2'-fluorobenzophenone,0.5 ml of triethylamine and 0.23g (0.0036 M) of ethanolamine in 15 ml ofbenzene was kept at room temperature for 65 hours and then waspartitioned between 25 ml of ethyl acetate and 25 ml of water. Theorganic layer was separated, washed with saturated brine, dried overanhydrous sodium sulfate and evaporated to dryness. The residue waspartioned between 20 ml of ether and 20 ml of 1N hydrochloric acid. Theacid layer was separated and extracted with 25 ml of ethyl acetate. Theorganic layer was then washed with 20 ml of dilute ammonium hydroxide,dried over anhydrous sodium sulfate and evaporated to dryness. Theresidual oil was crystallized from ether and recrystallized from amixture of methanol and water to give the above named product as whiteprisms, m.p. 120°-123°.

EXAMPLE 31 Preparation of10-Chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one

A solution of 0.5g (0.0012 M) of7-(2-acetoxyethyl)-10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-onein 5 ml of methanol was treated with 2 ml of 3N sodium hydroxide. After3 hours, 50 ml of water was added and the solution was extracted with 40ml of dichloro-methane, which was then dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was crystallized from amixture of methanol and water to give10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one as white prisms, m.p. and m.m.p. 141°-146°.

EXAMPLE 32

The pharmacological activity of a series of compounds of the presentinvention was determined in standard screening tests. Compounds whichwere employed in these experiments were as follows:

10-chloro-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydro-11-b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(7H)-one(COMPOUND A) and

10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6-(7H)-one(COMPOUND B).

The tests employed in this experiment were the following:

Foot Shock

This test is a screen for compounds having muscle relaxant and/oranti-anxiety (tranquilizer) activity. A pair of mice is confined under a1 liter beaker placed on a grid which presents shock to the feet. Atleast five fighting episodes are elicited in a two-minute period. Pairsof mice are marked and pretreated by oral dosage 1 hour prior to asecond shocking. Logarithmic-dose intervals are utilized up to a maximumof 100 mg/kgm. At the 100 percent blocking dose, three out of threepairs must be blocked from fighting.

Inclined Screen

The test is useful in determining muscle relaxant and/or sedativeactivity. Groups of six male mice are given the test drug (maximum doseof 500 mg/kg.) and then are left on the inclined screen at least 4 hoursfor observation of paralyzing effects severe enough to cause them toslide off the screen. If activity is observed, additional doses aretested until at least two are reached at which some, but not all theanimals slide off the screen. Doses at which mice fall off the screendue to toxicity or excitation are not included in the calculation ofPD₅₀. The PD₅₀ is determined from a graph on which dose is plottedagainst percent of mice paralyzed. This PD₅₀ value is defined as thedose in mg/kg. which can be expected to cause 50 percent of mice toslide off the screen.

Unanesthetized Cat

Cats are treated orally and observed for minimum symptoms -- usuallyataxia. One cat is used at a dose of 50 mgm/kgm. If activity is present,up to three cats/dose are used. Results are given as minimum effectivedose. This test is useful in determining muscle relaxant activity.

Antimetrazol

This test determines anticonvulsant and/or sedative activity ofcompounds in mice. The test compound is administered orally to groups offour mice at various dose levels. One hour later, metrazol (at a doselevel previously determined to be sufficient to induce convulsiveseizures in all test animals ˜ 125 mg/kg.) is administeredsubcutaneously and the animals are observed for protection fromcompulsive seizures. Results are recorded as the number of animalsprotected against convulsions. The dose at which 50 percent of theanimals are protected from convulsive seizures is expressed as the ED₅₀.

The test results from the above tests using indicated compounds of thepresent invention are summarized below in Table I.

                                      TABLE I                                     __________________________________________________________________________            Footshock                                                                     100% Blocking                                                                           Inclined Screen                                                                         Unanesthetized                                                                         Antimetrazol                             Compound                                                                              Dose Level                                                                              PD.sub.50 Cat MED  ED.sub.50                                __________________________________________________________________________    Compound A                                                                            20 mg.    50 mg.    5 mg.    --                                       Compound B                                                                             4 mg.    15 mg.    5 mg.    2.034 mg.                                __________________________________________________________________________

Example 33

COMPOUND B(10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6-(7H)-one) was prepared in the form of several pharmacological formulationsas follows:

    ______________________________________                                                                Per 1.3 Gm.                                           A. Suppository Formulation                                                                            Suppository                                           ______________________________________                                        10-Chloro-11b-(2-fluorophenyl)-7-                                             (2-hydroxyethyl)-2,3,5,11b-tetrahydro-                                        oxazolo[3,2-d][1,4]benzodiazepin-6-                                           (7H)-one                0.010 Gm.                                             Wecobee M*              1.245 Gm.                                             Carnauba Wax            0.045 Gm.                                             ______________________________________                                    

Procedure:

1. The Wecobee M and the carnauba wax were melted in a suitable sizeglass-lined container (stainless steel may also be used), mixed well andcooled to 45°C.

2. The 10-Chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6-(7H)-one which had beenreduced to a fine powder with no lumps, was added and stirred untilcompletely and uniformly dispersed.

3. The mixture was poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 Grams.

4. The suppositories were cooled and removed from molds. They were thenindividually wrapped in wax paper for packaging (foil may also be used).

    ______________________________________                                        B. Capsule Formulation  Per Capsule                                           ______________________________________                                        10-Chloro-11b-(2-fluorophenyl)-7-                                             (2-hydroxyethyl)-2,3,5,11b-tetra-                                             hydrooxazolo[3,2-d][1,4]-benzodiazepin-                                       6-(7H)-one              10 Mg.                                                Lactose, U.S.P.         165 Mg.                                               Corn Starch,U.S.P.      30 Mg.                                                Talc, U.S.P.            5 Mg.                                                 Total Weight            210 Mg.                                               ______________________________________                                    

Procedure

1.10-Chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]-benzodiazepin-6-(7H)-one,lactose and corn starch were mixed in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a No. 1A screen with knives forward.

3. The blended powder was returned to the mixer, the talc added andblended thoroughly.

4. The mixture was filled into No. 4 hard shell gelatin capsules on aParke Davis capsulating machine. (Any similar type capsulating machinemay be used.)

    ______________________________________                                        C. Parenteral Formulation                                                                           Per cc                                                  ______________________________________                                        10-Chloro-11b-(2-fluorophenyl)-7-                                             (2-hydroxyethyl)-2,3,5,11b-tetra-                                             hydrooxazolo[3,2-d][1,4]-benzo-                                               diazepin-6-(7H)-one   5.0       Mg.                                           Propylene Glycol      0.4       CC.                                           Benzyl Alcohol (Benzaldehyde free)                                                                  0.015     CC.                                           Ethanol 95 percent U.S.P.                                                                           0.10      CC.                                           Sodium Benzoate       48.8      Mg.                                           Benzoic Acid          1.2       Mg.                                           Water for Injection  q.s.                                                                           1.0       CC.                                           ______________________________________                                    

Procedure (For 10,000 cc)

1. The 50 Grams of10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]-benzodiazepin-6-(7H)-onewere dissolved in 150 cc of benzyl alcohol; 4,000 cc of propylene glycoland 1,000 cc of ethanol were added.

2. The 12 Grams of benzoic acid were dissolved in the above. The 48.8Grams of sodium benzoate dissolved in 3,000 cc of Water for Injectionwere added. The solution was brought up to final volume of 10,000 ccwith Water for Injection.

3. The solution was filtered through an 02 Selas candle, filled intosuitable size ampules, gassed with N₂ and sealed. It was then autoclavedat 10 psi for 30 minutes.

    ______________________________________                                        D. Tablet Formulation    Per Tablet                                           ______________________________________                                        10-Chloro-11b-(2-fluorophenyl)-7-                                             (2-hydroxyethyl)-2,3,5,11b-tetra-                                             hydrooxazolo[3,2-d][1,4]-benzo-                                               diazepin-6-(7H)-one      25.00 Mg.                                            Dicalcium Phosphate Dihydrate, Unmilled                                                                175.00 Mg.                                           Corn starch              24.00 Mg.                                            Magnesium Stearate       1.00 Mg.                                             Total Weight             225.00 Mg.                                           ______________________________________                                    

Procedure

1.10-Chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]-benzodiazepin-6-(7H)-oneand corn starch were mixed together and passed through an No. 00 screenin Model "J" Fitzmill with hammers forward.

2. This premix was then mixed with dicalcium phosphate and onehalf ofthe magnesium stearate, passed through a No. 1A screen in Model "J"Fitzmill with knives forward, and slugged.

3. The slugs were passed through a No. 2A plate in a Model "D" Fitzmillat slow speed with knives forward, and the remaining magnesium stearatewas added.

4. The mixture was mixed and compressed.

We claim:
 1. A compound of the formula ##STR37## wherein R₁ is hydrogen,nitro, trifluoromethyl, halogen, lower alkyl, lower alkyl mercapto orlower alkoxy; R₃ is hydrogen, or lower alkyl; R₅ is pyridyl; R₂₂ is anysuitable protecting group selected from the group consisting of the acylmoiety of a lower alkanoic acid and carbobenzoxy; m is an integer from1-7; A is selected from the group consisting of --CH₂ -- and ##STR38##and X' is chlorine, bromine or iodine.